TRPM3 is a calcium-permeable, nonselective TRP channel expressed in somatosensory neurons, including nociceptors. Several lines of evidence, including preclinical and human genetic data, implicate TRPM3 in pain signaling and migraine. BHV-2100 is a first-in-class TRPM3 antagonist in development for pain and migraine that has demonstrated potent pain reversal in preclinical models.

Assess the safety, tolerability, and pharmacokinetics of BHV-2100.

This was a randomized, placebo-controlled, sequential single and multiple ascending dose (SAD/MAD) study. Healthy adults aged 18-55 years were enrolled. SAD participants were randomized 3:1 to single dose BHV-2100 (25, 75, 150, 250, or 500mg) or placebo under fasting conditions; 150mg was also tested with food and famotidine. MAD participants were randomized 3:1 to BHV-2100 (25, 75, 150mg once-daily or 150mg twice-daily) or placebo and treated for 14 days. Safety and pharmacokinetics were evaluated.

In the SAD and MAD cohorts, 39 and 32 participants were treated, respectively. AEs occurring in >1 participant across pooled BHV-2100 SAD doses included dizziness and fatigue, each occurring in 2/30 BHV-2100-treated participants and 0/9 placebo-treated participants. No AEs occurred in >1 participant across BHV-2100 MAD doses. No serious or severe AEs were reported. Most AEs were mild and resolved spontaneously without treatment. No clinically significant trends in vital signs, laboratory values, or ECGs were observed. Plasma concentrations exceeded EC₉₀ after 20 minutes and were sustained above EC₉₀ for several hours at all dose levels. T_max was 1.5-2 hours; half-life was 8-12 hours. Once-daily 75mg provided plasma concentrations >EC₅₀ over 24 hours; 150mg twice-daily provided >EC₉₀ over 24 hours. Dosing with food or famotidine did not significantly impact pharmacokinetics.

TRPM3 represents a novel target for the treatment of pain and migraine. BHV-2100 demonstrated excellent safety and pharmacokinetics and is being evaluated in clinical trials for pain (EudraCT 2024-512187-57) and migraine (NCT06603623) as a novel non-opioid treatment.